Literature Review

Neuroprotective Effects Against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

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DOI: 10.4137/JEN.S33444
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Abstract
Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surgery in elderly patients. While often reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into Alzheimer's disease. Anesthetics have been implicated in POCD, as has neuroinflammation, as indicated by cytokine inflammatory markers. Photobiomodulation (PBM) is an effective treatment for a number of conditions, including inflammation. PBM also has a direct effect on microtubule disassembly in neurons with the formation of small, reversible varicosities, which cause neural blockade and alleviation of pain symptoms. This mimics endogenously formed varicosities that are neuroprotective against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be effective as a preconditioning treatment against POCD; similar to the PBM treatment, protective and abscopal effects that have been demonstrated in experimental models of macular degeneration, neurological, and cardiac conditions.
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1JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
Neuroprotective Effects Against POCD by
Photobiomodulation: Evidence from Assembly/
Disassembly of the Cytoskeleton
Ann D. Liebert1, Roberta T. Chow2, Brian T. Bicknell3 and Euahna Varigos4
1University of Sydney, Sydney, NSW, Australia. 2Brain and Mind Institute, University of Sydney, Sydney, NSW, Australia. 3Australian Catholic
University, Sydney, NSW, Australia. 4Olympic Park Clinic, Melbourne, VIC, Australia.
ABSTRACT: Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surger y in elderly patients. W hile often
reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into A lzheimer’s disease. Anesthetics have
been implicated in POCD, as has neuroina mmation, as indicated by cytokine inammatory markers. Photobiomodulation (PBM) is an eective treatment
for a number of conditions, including inammation. PBM also has a direct eect on microtubule disassembly in neurons with the formation of small,
reversible varicosities, which cause neural blockade and alleviation of pain symptoms. is mimics endogenously formed varicosities that are neuroprotec-
tive against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be eective as a precon-
ditioning treatment against POCD; similar to the PBM treatment, protective and abscopal eects that have been demonstrated in experimental models of
macular degeneration, neurological, and cardiac conditions.
KEYWORDS: photobiomodulation, PBM, postoperative cognitive dysfunction, POCD, cytoskeleton, neuroprotection
CITATION: Lieber t et al. Neuro protect ive Effec ts Against POCD by Photobiomodulation:
Evidence from Assembly/Disassembly of the Cytoskeleton. Journal of Experimental
Neuroscience 2016:10 1 –19 doi:10.4137/JEN .S33 444.
TYPE: Review
RECEIVE D: August 26 , 2015. RESUBMITTED: Decemb er 9, 2015. ACCEP TED FOR
PUB LI CAT IO N: D ece mber 15 , 2015.
ACADEMIC EDITOR: Lora Talley Watts, Edito r in Chief
PEER REVIEW: Four peer review ers cont ributed t o the peer re view repo rt. Revi ewers’
repor ts total ed 1337 words, ex cluding a ny conde ntial co mments to t he acade mic
editor.
FUNDING: Authors disclose no external funding sources.
COMPET ING INTE RESTS: BT B is an agent fo r Irradi a AB, a com pany that man ufactur es
therap eutic las er instru ments. A DL, RC, and E V hold a pate nt (PCT/AU2015/0 0688) that
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CORRESPONDENCE: brian.bicknell@acu.edu.au
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Introduction
Postoperative cognitive dysfunction (POCD) is a neurode-
generative condition, acquired after surgery and anaesthe-
sia,1,2 and is similar to Alzheimer’s disease (AD) in symptoms
and risk factors such as age and education level.1,3 POCD
has become a signicant problem in the health-care system,
in terms of both patient outcome and increased resources
expended. As yet, there a re a few eective therapeutic inter ven-
tions. Photobiomodulation (PBM) is the use of (nonthermal)
visible and infrared light to promote therapeutic benets.4–6
Recently, PBM has been shown to be eective against neu-
rodegenerative disorders, including AD,7 Parkinson’s disease
(PD),8 and depression,9 in both animal models and clinically.
e concept of preconditioning in health with laser treatments
has been explored over the past few years with increasing evi-
dence of its eectiveness.10 is paper reviews the eects of
PBM treatment on the cytoskeleton as a mechanism behind
preconditioning and its proposed use for preconditioning and
neuroprotection against POCD. Cytoskeleton modulation,
as well as the parallel between the evoked PBM response
and endogenous mechanisms of neuroprotection in hiber-
nation, cortical spreading depression (CSD), N-methyl--
aspartate (NMDA) poisoning, and ischemic preconditioning,
is reviewed. ese mechanisms involve interaction between
a number of proteins and signaling molecules, including
TWIK-related spinal cord potassium channels (TRESK) and
transient receptor potential vanilloid 1 (TRPV1) ion channels.
ese proteins may interact with the cytoskeleton,11,12 post-
synaptic density protein 95 (PSD-95), cypin, and prion protein
(PrPC), which together organize cytoskeleton structure.13–1 5
is review discusses the role of the cytoskeleton in allostasis
in response to redox stress and cellular stress,15,16 which results
in neuroinammation17 and protein interactions of the axonal
and synaptic densities.18 PBM has been shown to have a direct
eect on the cytoskeleton, which is directly involved in neural
blockade, in pain modulation19 and most probably in the pre-
conditioning eects of PBM, which may also be important
in preconditioning against POCD. e emphasis is on the
neuroprotective role of small, reversible axonal varicosities
that are protective against the large destructive neural vari-
cosities seen in neurodegenerative disease and sympathetically
dysregulated pain.
Postoperative Cognitive Dysfunction
POCD is also known, in the literature, as postoperative
cognitive decit, postoperative cognitive decline, periopera-
tive cognition decit, and postoperative cognitive change. It
is a widely recognized clinical condition, involving the loss
Journal name: Journa l of Experimental Neuroscience
Journal ty pe: Review
Yea r: 2 016
Volume: 10
Runni ng head verso: Liebert et al
Runni ng head recto: Neuroprotective eects agai nst POCD by photobiomodu lation
Liebert et al
2JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
of cognition following anaesthesia and surgery. Although
POCD has been extensively reviewed,1,20–2 4 it has no
universally accepted denition. In fact, there is no Interna-
tional Statistical Classication of Disease code for POCD,
Diagnostic and Statistical Manual of Mental Disorders code,
gold standard diagnostic criteria, and recognized biomarker.22
However, the perception of POCD as a problem and a con-
sequence of anaesthesia and surgery has been recognized
since 1860 when Bigelow rst used anesthetics.25 POCD has
been increasingly documented since 195526 and has been well
described as an objective diagnosis.27 An operational under-
standing of POCD is its manifestation as an acute but often
subtle deterioration in cognition, with a loss of the ability to
perform tasks involved with everyday living. It may aect a
spectrum of cognitive abilities, including memory, speed of
information processing, orientation, concentration, psycho-
motor ability, ne motor coordination, and attention span.
POCD is observed in patients as the inability to accomplish
simple cognitive tasks, such as crosswords,1 and is diagnosed
using a variety of neuropsychological tests. Denitive diag-
nosis requires that the tests be performed preoperatively, in
order to obtain a baseline from which a decline can be deter-
mined. Postoperative tests are best performed one week after
surgery, after any postoperative delirium has passed, and after
the cessation of any drugs and pain that might cause interfer-
ence in the testing. Most studies20,27,28 agree that the major
factors that inuence POCD are increasing age (.60 years,
although some studies use .65 years or even .70 years),
preoperative cognitive condition, and education. Cognitive
reserve and trajectory are perhaps the most important factors
that inuence the risk of POCD.29 Additional factors include
length and complexity of the surgery (with cardiac surgery
possibly being more risky than noncardiac surgery),20,28 a
history of alcohol abuse,30 previous stroke,28 diabetes mellitus,
hypertension, atherosclerosis,31 and postoperative complica-
tions, especially respiratory complications and postoperative
infections.27 Arecent study has also identied gender as a fac-
tor, with females being at greater risk than males,32 as is the
case with AD.33 Although POCD in the very young is less
studied, most evidence, such as that obtained from twin stud-
ies34 and cohort studies,35 suggests that it is much less of a
problem. However, Yin et al determined that propofol could
impair short-term memory in children.36
Although there have been numerous studies that have
reported POCD, many of these are anecdotal, are case
studies, or are poorly controlled and inadequately tested.
Some clinicians and researchers consider that there is a lack of
statistical evidence to separate POCD from normal cognitive
decline and reviews of case-controlled studies using stringent
criteria have shown mixed results in the past.22 For example,
a review of 25 randomized controlled trials did not demon-
strate unequivocal POCD response in patients37 and a meta-
analysis of 26 randomized controlled trials found no evidence
of POCD.38 Part of the diculty in the study of POCD is the
variety of testing regimes and diagnostic tools that have been
used in various studies and the consequent inability to com-
pare between studies. Other diculties include the lack of
appropriate control groups in many studies and the diculty
in determining the normal cognitive trajectory of surgery
patients in the studies.22 In addition, many of the studies in
the past have been small, lacked power, and were retrospec-
tive. Despite these problems, there is compelling evidence
that POCD exists as a genuine phenomenon21,37,39 with a
strong public and medical awareness of the consequences of
the disorder. Recent prospective studies of POCD have indi-
cated that the risk of POCD posed by anaesthesia/surgery was
1.3540 and 1.9941 compared with the general population. In
recent years, a number of prospective, long-term, and cohort
studies have been initiated in order to provide more denitive
information and predictions for POCD.
e general acceptance of POCD as a real and measur-
able disorder has resulted in increased attention and research
into the implications of POCD. Each day, millions of people
around the world undergo anaesthesia and surgery. Increas-
ing life expectancy and the consequent increase in the elderly
population, the advances in surgical procedures, the decline in
mortality rates, and the shortening of postoperative recovery
times point to an increasing number of surgical procedures
performed on the elderly, the population most at risk of
POCD. For example, statistics from the Australian Institute
of Health and Welfare (http://www.aihw.gov.au/) indicate
that in 2010, 32% of all anesthetics were given to.65years
old (13.5% of population). With the predicted percent-
age of .65 years old in the population in 2051 increasing
to 24.2%, anesthetics given to .65 years old is predicted to
be 48% of all anesthetics administered. In addition to being
major recipients of surgical procedures, elderly patients are at
greater risk of cognitive decline and dementia, pointing to an
increasingly important role for POCD in the postoperative
recovery of elderly patients.
e reported incidence of POCD varies widely with
dierent studies, most probably reecting methodological
dierences. Incidence can range from 10% to 40% after
one week and up to 15% after three months postoperatively
in noncardiac surgery. e International Study of POCD
(ISPOCD) has concluded that 26% of patients older than
60 years developed POCD at one week postoperatively and
10% had POCD at three months.27 Although it has been
commonly accepted that cardiopulmonary bypass surgery
has a higher risk of POCD than noncardiac surgery,20,28 this
might in fact be due to the generally less rigorous criteria
used in many cardiac surgery studies,22 the dierences in
diagnostic criteria21 or to specic factors common to cardiac
surgery. Evered et al42 found that at three months, the number
of patients with POCD were independent of whether the
surgery was cardiac or total hip replacement and, in general,
the number of patients with POCD at three months are
similar in both groups.23
Neuroprotective effects against POCD by photobiomodulation
3JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
POCD may be short-lived and reversible or may last for
months or possibly years, with the potential to aect clinical
outcomes for up to ve years postoperatively.43 While up to
47% of elderly patients could demonstrate some cognitive
decline after 24 hours, this decreases to much lower levels
by the time of discharge.21 Early POCD, lasting up to three
months, may in fact be a common problem, aecting not only
up to 10% of elderly surgery patients but also young patients,
but in whom recovery is much faster.21 Recovery from POCD
sets this condition apart from other neurodegenerative dis-
eases (AD, PD, etc.) and the recovery is similar (albeit much
slower) to the recovery in cognitive decline that occurs within
hours after CSD that accompanies migraine with aura and
cluster headaches.44
POCD may also be progressive, with some patients who
do not show early POCD at one week, progressing to POCD
at three months. POCD might also be cumulative, with more
episodes of anaesthesia/surgery leading to a greater incidence
of POCD.31 Even if there is complete recovery from POCD,
the eects of short-term POCD impact on patients’ quality
of life and the ability to continue in employment. ere is,
therefore, a socioeconomic burden, including increased hos-
pital stays, increased out of hospital care, job loss, and depen-
dence on social payments.45 ere may also be an increase in
mortality, with POCD patients 1.63 times as likely to die as
non-POCD patients.45
Persistent POCD is more contentious. Some studies have
shown evidence of persistent POCD in a small number of
patients. e ISPOCD showed that after one to two years, 1%
of patients showed persistent POCD.46 Some early studies indi-
cated that dementia was still apparent after ve years,47 with
one study showing high levels of long-term POCD (42%) at ve
years.48 e ISPOCD long-term study found, however, no sig-
nicant relationship with dementia after 11years,49 and other
studies have shown little evidence of cognitive decline after a
number of years when compared with nonsurgery patients.50–52
e cause or causes of POCD have remained elusive,
despite intensive research over the past 25 years. As with other
forms of dementia, the cause of POCD is almost certainly
multifactorial. Part of the diculty in determining etiologi-
cal factors involved in POCD is in the separation of anaes-
thesia, surgery, and perioperative care; it is not usual to give
anaesthesia without surgery and surgery is most usually per-
formed under anesthetic. e time in hospital may also be a
factor, the so-called hospital stay syndrome.53 Other contrib-
uting factors to POCD may include perioperative conditions,
inammation, pain, and comorbidities, although a number of
specic factors, such as changes in cerebral blood ow, car-
diopulmonary bypass, hypoxemia, and microemboli, have
been all but discarded as sole causes.23 In reviewing avail-
able evidence, Krenk et al21 suggest a multifactorial patho-
genesis with the potential involvement of postoperative sleep
disturbance (exacerbated by opioid analgesia), inammatory
stress response, pain, and environmental factors. Fast-track
hip and knee replacements, which included patient education
and preparation, as well as shorter hospital stays, were shown
to result in decreased short-term POCD, but not long-term
POCD.54
POCD shows some similarities with other forms of
dementia, such as A D, which it mimics in a number of ways 3,55,56
and POCD may in fact be triggered by AD pathways.55 Mild
cognitive impairment (MCI) is a subjective decline in cogni-
tion and can be a precursor to AD, with a substantial minority
with MCI (depending on age) progressing to AD.57 MCI is
prevalent in the elderly population with between 14% and 18%
of people over 75 showing symptoms.23 Since a substantial pro-
portion of elderly patients undergoing surgery will have MCI,
it is possible that anesthetics and surgery could aggravate or
unmask MCI and lead to progression to POCD and ultimately
to AD. Aging of proteins and an increase in misfolded and
unrectied proteins lead to an increase in protein-folding neu-
rodegenerative diseases (such as AD, PD, Huntington’s disease
(HD), and prion diseases) and are most probably also linked
with POCD.13,58 ere is currently a great deal of research into
the link between POCD, anaesthesia/surgery, and dementia,
especially AD, since any connection would indicate a far
greater and longer lasting impact of POCD.
e exact mechanism of action of anaesthesia is still
unclear. General anesthetics have a number of common
receptors in the central nervous system, including either
blocking NMDA receptors (eg, ketamine and nitrous oxide)59
or enhancing gamma-aminobutyric acid type A (GABAA)
receptors.60 e fact that these receptors are known to aect
memory61,62 raises the possibility of a direct link bet ween anes-
thetics and POCD. Cell culture studies indicate that a num-
ber of anesthetics cause apoptosis39 and mounting evidence
from animal studies has strengthened the link between anes-
thetics and dementia including POCD.55,63 –65 For example,
anaesthesia has been shown to cause cognitive decit and
neurodegeneration in developing (rat) brains,66 –68 and vanil-
loid anaesthesia has been shown to lead to long-term memory
impairment in adult and aged rats69 and mice,70 as well as a
transient decrease in the expression of hippocampal neuro-
nal nitric oxide synthase (nNOS) and PSD-95 in aged rats,
together with cognitive impairment.71 Anaesthesia and cog-
nitive decit in animal studies has been linked with NMDA
receptor expression,72 disruption of calcium homeostasis,73
and neuroinammation (see the following sections). Although
many studies emphasize the potential link between anesthet-
ics and cognitive decline, Callaway et al found no link between
sevourane and long-term cognitive impairment in aged rats74
and found that the eects of desurane were dose dependant
and not long lasting.75
A number of neurodegenerative diseases (AD, PD, HD,
tauopathies) have in common the disruption of the cytoskel-
eton, with the disassembly of microtubules (MTs) and the
concomitant accumulation of tau brils and b-amyloid (Ab).
Anesthetics are known to interact with the cytoskeleton,64 ,76–79
Liebert et al
4JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
can bind to tubulin and cause MT disassembly,80 and so are
appropriate targets as potential causative agents of POCD.
Craddock et al80 have identied multiple (32) binding sites
for volatile anesthetics on a- and b-tubulin and consider
that anesthetics are prime candidates as causative agents
of POCD, via altered tubulin and phosphorylation of tau,
leading to MT instability. Animal studies have also sug-
gested that anesthetics (propofol, halothane, sevourane,
and isourane) can increase AD b-amyloid24, 63,8 1–83 and
increase tau phosphorylation70,84,85 with the anesthetic sevo-
urane shown to produce transient hyperphosphorylation of
tau in mice on a single application and persistent tau hyper-
phosphorylation and memory impairment with repeated
exposure.84 e anesthetic propofol was also shown to induce
tau hyperphosphorylation in a mouse hippocampus model of
AD.86 On the other hand, exposure of presymptomatic AD
mice to anesthetics (halothane, isourane) did not accelerate
the progression of the disease but, on the contrary, appeared to
result in the preconditioning against neurodegeneration, due
to increased phosphorylation of tau.87
Despite anecdotal and some epidemiological evidence of
a link between anesthetics and AD,88 PD,89–91 and POCD,92
clinical evidence does not, on the whole, support the animal
studies. Large studies such as the ISPOCD93 as well as meta-
analyses94,95 have found no link between anesthetics and
POCD or AD, including comparisons between general and
regional anesthetics.93,96 However, an expert group attending
the British Journal of Anaesthesia Salzburg Seminar in 2012
reviewed the available data on POCD and concluded that
there was mounting evidence to indicate that general anaes-
thesia can negatively aect cognition especially in the elderly
(as well as the very young).70,97 Although there is little direct
evidence that the type of anesthetic is a risk factor,3 7,70 it is
possible that the route of anesthetic and depth of anaesthesia
may have an impact on POCD. e use of the bispectral
index to guide anesthetic titration has been found to reduce
the occurrence of POCD in some studies.98,99 ere are also
indications that it is not simply anesthetic use that leads to
POCD. Surgery-induced nociception without anesthetics was
shown to induce POCD in mice.100
ere are a number of studies that have shown that
surgery/anesthetics can lead to increases in the biomarkers
for AD,85,101 including b-amyloid102 ,103 and phosphorylated
tau,101,103 strengthening the case for some involvement of anes-
thetics w ith the risk of A D.89,9 0 e presence of brai n b-amyloid
has in fact been found to be a good predictor of POCD risk in
cognitively normal patients.104 A consensus statement issued
from an international workshop on anesthetics and AD105
concluded that there was sucient evidence to warrant further
investigations into the onset and progression of AD and neu-
rodegeneration after anaesthesia and surgery and that clini-
cal trials should be emphasized, which are led by anesthetists.
Anesthetic delivery to patients undergoing surgery has always
been a highly individualized process. is individual approach
is amplied in elderly and other at-risk patients. ere as yet
have been no studies of POCD in groups that require dierent
anesthetic regimes, such as redheaded women.106 e focus of
research on POCD is moving from anaesthesia and surgical
techniques that are common to all patients and moving toward
individual patient-centered factors.2
e molecula r mechanism of POCD (as with other neuro-
degenerative diseases) has been dicult to pin down. Induced
POCD in mice has been shown to reduce NMDA receptor B
levels,100 which, along with PSD-95, is implicated in synaptic
plasticity and learning.107 Recently, aspartic acid, an agonist
and activator of NMDA receptors which implicated in AD,108
has been identied as a possible biomarker of POCD in aged
rats.109 POCD was found to be linked with endogenous mela-
tonin levels and possibly circadian rhythms in patients who
had undergone abdominal surgery.110 Proteomics has provided
a window into possible molecular mechanisms of POCD and
other neurodegenerative diseases. Lietal, in a study of aged
rats with cognitive dysfunction following anesthetic and sur-
gery, identied 21 proteins that were altered (upregulated
or downregulated) following surgery/anaesthesia.111 Four of
these proteins were involved in oxidative stress, seven proteins
with mitochondrial energy production, and three proteins
were implicated in neuroinammation. Kalenka et al11 2 found
that 17 proteins dierentially expressed in rat hippocampus
after isourane anaesthesia, including proteins involved in
stress response and cytoskeleton integrity. In a clinical pro-
teomic study, 58 separate polypeptides were found to have
changed expression in patients identied with POCD fol-
lowing surgery.113 Interestingly, in a proteomic study of twins
with no symptoms of AD, mitogen-activated protein kinase
(MAPK) was found to be related to early cognitive decline
over a 10-year period.114
Neuroinammation may play a role in POCD,2,115 –118
as pain119 and alleviation of each may reduce short-term
POCD.118,12 0 Injury and insult lead to the formation of an
inammasome, which initiates an inammatory cascade
involving inammatory cytokines, including interleukin-1b
(IL-1b), IL-6, tumor necrosis factor-a (TNF-a), and nuclear
factor kappa enhancer of activated B cells (NF-kB), regulated
by alpha-melanocyte-regulating hormone (a-MSH). e
involvement of the inammatory response in POCD is sug-
gested by a number of animal studies. Anaesthesia alone and
anaesthesia combined with surgery can induce IL-1b121–125
and TNF-a123 in mouse and rat models of POCD. Isourane
without surgery has also been shown to increase TNF-a,
IL-6, and IL-1b in mice.126 Li et al,111 identied three pro-
teins that were involved in neuroinammation.
e link between inammatory cytokines and POCD is
also suggested by clinical studies, which parallels the suggested
association bet ween inammatory cytokines and AD.127 High-
mobility group box 1 and IL-6 were found to be signicantly
correlated with POCD in patients who had undergone major
surgery,128 while Ji et al129 found that IL-1b (but not IL-6)
Neuroprotective effects against POCD by photobiomodulation
5JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
was associated with POCD in total hip replacement surgery.
Inammation markers 1L-6, IL-1b, TN F-a, S-100B, and
tau were also found to increase after surgery.103 Recent studies
have also shown some link between POCD in patients and
levels of insulin-like growth factor 1 (IGF-1) and IGF-1 bind-
ing protein 7, both were believed to be important in memory
consolidation and AD.17 IL-6 has been suggested as playing
a crucial role in the neuroinammatory response leading to
POCD.130 Inammatory cytokines have also been associated
with POCD after cardiac surgery131 and levels of S-100, an
indicator of traumatic brain injury, was found to be an indica-
tor of POCD.132,133 In addition, in a meta-analysis of studies
investigating the inammatory response of patients, IL-6 and
S-100B were identied as being correlated with POCD.134 e
inammatory cascade is, in part, controlled by the melanocor-
tin system including a-MSH, which downregulates inam-
matory cytokines.135 Melatonin is important as a risk factor of
AD136 and possibly POCD.110 e melanocortin system also
has a PrPC regulatory involvement137 and Mariante et al138
contend that PrPC is involved in a regulatory loop of inam-
matory processes linked with systemic or cellular stress.
ere is a need to identify patients at risk of POCD,
but as yet, no common genomic indicators of POCD have
been unambiguously identied. is includes apolipoprotein
E (ApoE), which has been associated with POCD in some
studies139 but not in others,140 ,141 although a recent prospective
study has shown that patients carrying the ApoE4 genotype
(the highest genetic risk factor for AD)142 had an increased risk
of POCD.143 A review of the literature has identied a number
of potential markers of POCD,144 including C-reactive protein
(CRP), P-selectin (SELP), complement component 3 (C3F),
inducible NOS (iNOS), and cytochrome P450. e presence
of brain b-amyloid has also been found to be a good predictor
of POCD risk in cognitively normal patients104 and a link has
also been established between Ab42/tau ratio (an indicator of
AD) in the cerebrospinal uid of patients prior to surgery and
POCD.129,145 Proteomic studies have suggested that brino-
peptide A is a potential biomarker.113
Neuroprotection by preconditioning is the use of subletha l
insult to provoke a protective response and has had some suc-
cess in the prevention of ischemic stroke, AD, and PD in ani-
mal models.146 Neuroprotection against POCD has had mixed
success. Bilotta et al,37 based on a review of clinical trials, sug-
gest that neuroprotection against POCD could be achieved
with a number of drugs, such as atorvastatin. ere is some
evidence that amantadine, which increases glial-cell-line-
derived neurotrophic factor and decreases neuroinammation,
might reduce the eect of POCD.147 IL-6 receptor antagonists
have also been found to act as a preventative measure against
POCD.130 Remote ischemic preconditioning, however, was
not found to be eective as neuroprotection against POCD;148
nor was propofol (used to suppress electroencephalogram
bursts),149 reduction in C5 complement,150 platelet activating
factor antagonist151 or the corticosteroid dexamethasone.152
Presurgical cognitive intervention has been shown to have
some eect on reducing POCD.153 Interestingly, the adminis-
tration of melatonin prior to isourane anaesthesia in rats was
shown to reduce cognitive impairment.154
PBM has been shown to have an eect on neurodegen-
erative diseases in animal models, including AD, PD, and
depression.7,9,155,156 Purushothuman et al7 propose that the
ability of PBM to reduce hyperphosphorylation of tau is neu-
roprotective in AD. It has also been shown that laser light is
absorbed by b-amyloid,157 and Grillo et al158 have shown a
decrease in b-amyloid with PBM. It is therefore proposed that
the success of PBM in the preconditioning against AD and
the treatment of PD suggest that it might also be an eective
preconditioning agent against POCD.
Photobiomodulation
PBM has been dened as a “nonthermal process involving
endogenous chromophores that elicit photophysical (linear
and nonlinear eects) and photochemical events at various
scales, resulting in benecial photobiological responses.4
is is most often low-level laser therapy (LLLT) but may
also be a noncoherent light-emitting diode (LED). Light
was used in 1903 as a therapy for skin lesions, with an article
published by Finsen in the Lancet in 19031 59 reporting the
striking results of the use of red light treatment to prevent the
disgurement of smallpox scars, providing that the interven-
tion was at an early stage of the disease. Additionally, Finsen
was awarded the Nobel Prize in 1903 for the use of ultra-
violet (UV) light for the treatment of lupus vulgaris. Photo-
therapy as a treatment fell from favor until 1968 when Mester
et al rst showed that laser could stimulate wound healing
and hair growth in mice.160 Another early use of laser therapy
was the treatment of wound and skin lesions (radiation ulcers
following the Chernobyl nuclear accident using argon lasers
(450–530nm).161 Over the past 45 years, PBM in the visible to
infrared wavelengths (between 400 and 1072nm) has become
increasingly accepted as a therapeutic intervention, with
randomly controlled clinical trials as well as animal models
demonstrating a signicant role for LLLT in the treatment of
many conditions in veterinary as well as human patients. It has
also become apparent that there is a biphasic dose response for
LLLT, following the Arndt–Schulz curve,162 where increas-
ing dose corresponds to an increasing eect up to a maximum
(a dose window), after which further increasing dose evokes
a negative response. PBM is currently used to treat a variety
of radiation and chemotherapy-induced ulcers,163 as well as
oral and other wounds4,16 4 and wound infection.165 e useof
PBM therapy can protect against damage to the skin by UV
light as well as a number of other skin conditions, including
vitiligo, psoriasis, and herpes simplex.166 LLLT is used for
sports injuries,167 tendon repair,168 remodeling collagen bers
in tendon injuries,169 for lymphedema management,170 and for
acceleration of tooth movement during orthodontics.171 PBM
has been used in the treatment of cardiac disease and cardiac
Liebert et al
6JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
protection in animal models via the modulation of iNOS and
induction of mesenchymal stem cells.172–175
PBM has also been successfully used in the treatment
of both acute and chronic pain in the periphery176 ,177 and in
central ly mediated pa in states includi ng chronic neck pa in.178–181
e ability of photons introduced as LLLT to modify bio-
electrical signaling in peripheral nerves has been unequivo-
cally demonstrated in animal and human models.19,182is
is of primary importance in pain treatment as suppression of
action potentials in nociceptors is one of the mechanisms for
the direct analgesic eects of LLLT.177 Nociceptors are selec-
tively aected by laser irradiation, and it has been proposed
that this eect underpins the pain-relieving eects of LLLT
in the treatment of acute and chronic pain182 and the basis of
the local anesthetic eect of LLLT, which can be eective as a
pain block in such things as dental extraction.183
Most recently, there has been increasing evidence from
animal studies for the use of PBM in cognitive and neuro-
degenerative diseases, such as depression,9,184 traumatic brain
injury,185 AD,7,158,186–189 and PD.8,155,156,189,190 PBM has the
added benet of a wide dose window to achieve the eect and
no identied harmful eects, within the correct dose param-
eters and following the contraindication recommendations of
not directing PBM into eyes, over a carcinoma site or over a
fetus.191
LLLT has also been shown to have a role in neuro-
protection190 and preconditioning against such conditions
as muscle fatigue, inammation, and pain, as reviewed by
Agrawal et al,10 macular degeneration,192 ,193 preconditioning in
cardiac protection,172 PD190 and AD.7,18 6 In addition to target-
ing the site of the disease, this preconditioning and protection
can also involve an abscopal (indirect) eect, where the eect
is elicited by irradiating an area of the body remote from the
site of disease or injury.189,194 is has been shown to occur in
patients with macular degeneration, where the nonirradiated
eye experienced the same protection as the irradiated eye.193
e abscopal eect has also been shown for cardiac disease in
rats, where LLLT to a remote site (tibia) elicited a response
in protection against cardiac infarct,173 upregulating iNOS
and mobilizing c-kit+ cells to be recruited to the heart damage
site.172 ,174is abscopal eect has been shown to be at least as
eective as PBM at the site of injury.174 Tibial bone marrow as
a target also improved cognition in a mouse model of AD.188
LLLT delivered to the skull in mice was also shown to improve
AD b-amyloid and cognition.186 Johnstone et al8 ,155 have shown
neuroprotection in a rat model of PD, where remote precondi-
tioning produced a similar eect on trans-cranial LLLT. ey
propose a systemic eect with circulating cellular or molecular
factors to induce the abscopal neuroprotective eect. Keszler
etal suggest that direct application of LLLT to patients’ hearts
may not be necessary for the protection against cardiac isch-
emia due to this systemic eect.175
Current known mechanisms of LLLT action have been
well reviewed4,195,196 a nd include roles for cytoc hrome-c-oxidase
and mitochondrial energy production,196 retrograde mito-
chondrial signaling,197 NOS modulation,173,181,196 ,198,199
electron transfer via a redox reaction200 resulting in antioxi-
dant enzyme activity,201,202 restoration of balance between
pro- and antioxidant mediators by increasing peroxisome
proliferator-activated receptor expression and glutathione
concentration,203 modulation of hypoxia-inducible factor 1a
(HIF-1a),204 reduction in TNF-a,205 modulation of inam-
matory cytokines and ILs, NF-kB,206,207 IL-6, and IL-1b,208
modulation of growth factors IGF-1, and transforming
growth factor beta-1 (TGF-b1),201 modulation of opioid and
its precursor molecule proopiomelanocortin (the melano-
cortin signaling system),209 and cytokine abscopal eects.155
LLLT is known to downregulate the inammatory process210
by increasing antioxidants and decreasing oxidative stress,211
via the mechanisms described earlier and by increasing super-
oxide dismutase.201,203 PBM also directly aects the cell sig-
naling molecule MAPK.167, 2 12
In addition to the photon receptors for the mechanisms
described earlier, which includes the known chromophores of
melanin, avins, porphyrins, and cytochrome C oxidase,196
there may be a second group of interactions where physical per-
turbations by photons cause conformational changes in recep-
tor proteins4,194,213 especially in redox-sensitive proteins. is
perturbation involves a molecular switching mechanism214
which includes the receptor tyrosine kinases,195,215 ion chan-
nels such as TRPV1 channels, which can respond to visible
and infrared light,216,217 and potassium channels.218 Various
opsin proteins, which belong to the G-protein-coupled recep-
tor family, also act as photoreceptors. ese include rhodopsin
molecules in rod cells of the retina and in the skin,2 19 photop-
sins in cone cells of the retina, melanopsins in retinal ganglion
cells, encephalopsins (OPN3) in the brain,220 and neuropsin
(OPN5) in spinal tissue (eye, brain, testes, spinal cord).221
Light also regulates neuronal activity in the eye by direct
allosteric modulation of GABA and NMDA receptor pro-
teins, which directly inuence neuronal signaling, depending
on the redox state of the receptor.222,223is group of inter-
actions with receptors would involve physical perturbation of
the molecular structure in the skin and neural membranes to
facilitate the physiological function.4,19 4
ere has been less attention to the role of cytoskeleton
modulation as a primary LLLT mechanism. Evidence for the
role of LLLT in cytoskeleton modulation, pain attenuation,
and neurotransmission blockade has been demonstrated by
Chen et al224 and Chow et al.19,177 As the cytoskeleton is both
a receptor and an initiator of signal transduction, cytoskeleton
modulation by PBM is a candidate for the observed abscopal
eects of LLLT.
MT and Cytoskeleton Modulation
e cytoskeleton is an important component of all cells and
consists of the MT network, neurolaments, and actin la-
ments. MTs provide structural support, connect targets, and
Neuroprotective effects against POCD by photobiomodulation
7JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
act as a track to direct vesicle and organelle trac within
the cell. MTs are composed of a- and b-tubulin dimers and
have dynamic instability, where they grow and shrink, switch-
ing between assembly (rescue) and disassembly (catastrophe)
according to the need, and are thus in equilibrium with unpo-
lymerized a- and b-tubulin. is process allows rapid reorga-
nization of the MT cytoskeleton. In neurons, MTs are found
in the dendrites, cell body, and axon. In dendrites, MTs are
short and have a mixed polarity. In axons, MTs form bundles
of various lengths but with the same polarity,225 which is criti-
cal for neurite polarity and neurite growth226 as well as antero-
grade and retrograde transport.
e control of this dynamic instability is very complex
and as yet poorly understood but appears to be regulated in
part by multiple posttranslational modications to the tubu-
lin protein (eg, tyrosination, polyglutamylation, acetylation,
SUMOylation)225 and in part by MT-associated proteins
(M A Ps),227 which bind either tubulin or assembled MTs and
are thus either stabilizing or destabilizing for MTs. MAPs,
such as tau (in axons) and MAP2 (in dendrites), bind directly
to MTs and form transient interactions that stabilize the MTs
into the parallel arrays seen as bundles. Other MAPs can
promote assembly (eg, MAP4) or disassembly (eg, stathmin)
of MTs. Phosphorylation of tau is necessary for MT stabi-
lization, but under normal conditions tau phosphorylation
is limited.228 With increased phosphorylation, the extent of
binding to MT decreases. A number of neurodegenerative
diseases (such as AD, PD, and other tauopathies)229,23 0 are
characterized by hyperphosphorylation of tau, where up to
100% of the available sites in the protein are phosphorylated.
is destabilizes MTs and leads to the formation of intracellu-
lar aggregates (neurobrillary tangles).229 An example of this
is children in Mexico City, who are exposed to heavy pol-
lution, can develop hyperphosphorylation of tau and protein
changes (aggregates) in the brain, particularly if they have
ApoE variant gene, which is associated with adult AD.2 31 Tau
may also provide a link with the plasma membrane and play a
role in signal transduction.232
Other molecules that may inuence MT dynamics
include PrPC and PSD-95. PrPC is known to bind to tubulin,
stathmin, and tau233–235 and has been proposed as a major
player in MT assembly/disassembly.236 Schmitz et al237,238
have shown that PrPC plays a direct role in the organization
of the cytoskeleton, as well as cognition and behavior, as a
result of its relationship with neurolaments and MTs. Dys-
regulation (upregulation) of PrPC expression leads to hyper-
phosphorylation of tau and malformed stumpy neurites.239
PrPC overexpression is also believed to be involved in the
b-amyloid formation and cognitive dysfunction of AD via its
interaction with nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase at the membrane, inammatory cytokines,
and the subsequent alteration of actin laments.240 Interaction
between PSD-95 and cypin has also been proposed to regulate
MT organization in dendrites.14
MTs are central in cellular signaling and a major target of
signaling pathways to maintain the balance in their dynamic
instability and thus control cellular (neuronal) function. ey
are also an eector of downstream signaling, interacting
with other signaling molecules such as NFkB, extracellular
signal-regulated kinase 2, and MAPK and organizing signal
pathways.241 Linden et al242 have suggested that PrPC, with its
membrane scaolding connection to the extracellular matrix,
links a-tubulin, b-tubulin, and MT and is thus involved in
multicomponent signal transduction with a wide range of allo-
steric eects in physiology and pathophysiology. PrPC acts as a
redox sensor molecule for oxidative stress and triggers down-
stream processes.243 Goswami11 has suggested that a compo-
nent of MT signaling is centered around TRPV1 channels,
which are redox sensors for infrared stimuli.244 Potassium
leak channel TRESK may interact with cytoskeleton12 and is
believed to be one of the two-pore domain potassium (K2P)
ion channels that are important as targets for anaesthesia.245
MTs act as the scaold for anterograde and retrograde
axonal transport of organelles, vesicles, and proteins using
kinesin and dynein motor proteins. e normal functioning of
neurons depends on the integrity of the cytoskeleton for fast
axonal ow. Because MTs are subject to constant catastrophe
and rescue and because MT bundles are of dierent lengths,
axons can normally cope with intermittent disruptions to the
MT cytoskeleton. Varicosities or focal swellings form when
complete breakage of the MT cytoskeleton leads to a buildup
of cargo at the breakage point.246 Disruption of the cytoskel-
eton and varicosity formation has a profound eect on the
bioelectrical function of nerves. Mitochondria, which deliver
the adenosine triphosphate (ATP) required for many enzymes
and the generation of action potentials, are not able to move
along the cytoskeleton. Ion channels such as TREK247 and
other signaling molecules such as nerve growth factor (NGF)
and brain derived growth factor (BDGF) are also not able to
move along the MT in retrograde or anterograde cargo trans-
port, which has marked eects on signal transduction.248
Assembly and d isassembly of the neural (synapt ic) proteins
is also observed as a common process during hibernation in
mammals,249 where it is involved in reversible neuroplasticity
and resistance to neural damage. During hibernation, cell
bodies and dendritic spines shrink, synapses are lost, and syn-
aptic proteins and MTs250 are disassembled. ese proteins are
stored in the axon until required for reassembly, rather than
being degraded and then resynthesized de novo.249 Proteome
variations during hibernation and arousal indicate that cyto-
skeleton changes are the dominant protein changes.251 MT
disassembly is regulated by tau phosphorylation, which, in this
case, does not form the brils that are typical of the tau hyper-
phosphorylation seen in AD.252is regular disassembly/
reassembly of proteins leads to some memory loss in hiber-
nating ground squirrels when compared with non-hibernating
squirrels.249 Human hypothermia with circulatory arrest and
subsequent resuscitation can also commonly accompanied by
Liebert et al
8JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
some memory loss,253 similar to POCD. Using this hiberna-
tion evidence, Arendt and Bullmann have proposed a model
for cytoskeleton modulation in the process for neuroplasticity
in the hippocampus and other cortical synapses.254
e appearance of varicosities in axons appears to be
an endogenous mechanism that protects nerves from dam-
age, occurring as a response to multiple stimuli and stressors,
including mechanical stress, axonal damage, heat and cold,
toxins, and anesthetics. Originally considered as only a sign of
neuropathology, it is now apparent that varicosities are revers-
ible and neuroprotective.14, 255 ere are numerous examples
of neuroprotective varicosities. In the central nervous system,
sublethal hypoxia can lead to reversible dendritic beading,
which can be blocked by NMDA antagonists.256 Ikegaya
etal255 have shown that small reversible dendritic varicosi-
ties are produced endogenously as a response to a stressor and
can act as a neuroprotection against greater damage to the
neuron (Fig. 1A). Prevention of this response led to increased
neuronal damage, collapse of normal neural function, and
cell death. is same response has been demonstrated more
recently by Tseng and Firestein,14 where a toxic assault
(NMDA poisoning) resulted in the production of small pro-
tective varicosities (Fig. 1B), which, as long as the response
was early, rapid and reversible, prevented the formation of
larger, destructive neuronal swellings and neuronal death.
Varicosity formation depends on the induction of nNOS and
the interaction between PSD-95, cypin, and tau. Increased
cypin and decreased PSD-95 resulted in an increased
number of small protective varicosities, while decreased
cypin and increased PSD-95 resulted in the opposite14
Figure 1. Formation of neuroprotective endogenous varicosities: (A) confocal laser microscopy images of formation of dendritic varicosities
in rat hippocampus neurons treated with 30 mM NMDA;255 (B) immunouorescent images of formation of dendritic varicosities (arrows) in rat
embryo hippocampus neurons, immediately after exposure to 30 mM NM DA (5 minutes) and reversal of varicosities af ter recovery (60 minutes);14
(C) immunohistoc hemistr y image stained for tubulin, showing varicosity formation in embryonic DRG neurons in response to resiniferatoxin activation of
TR PV1;18 (D) two-photon laser scanning images, showing the transient increase in mouse neuron volume before (control), during spreading depression
(SD) and after recovery from SD, including a merged image (overlap) showing the overlap (yellow), before volume (green), and during CSD (red).259
Neuroprotective effects against POCD by photobiomodulation
9JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
is was suggested as a pathway in which MT cytoskeleton
is regulated by sublethal changes to dendrites. PSD-95 (as
well as nNOS) is also implicated in the remyelination process
of regeneration of peripheral axons in a rat injury model.257
e dopamine metabolite N-arachidonoyl-dopamine applied
to dorsal root ganglia (DRG) neurites resulted in varicosity
formation (Fig. 1C) implicating TRPV1 in the formation
process.18 Endogenous dopamine metabolites are relevant to
anesthetic induced responses.258
Neuroprotective cytoskeleton modulation is also present
during the CSD associated with migraine with aura and corti-
cal trauma (involving TRESK polymorphisms), where neurons
undergo a transient volume increase2 59 (Fig. 1D). ese are seen
as part of the neuroprotective process that protects the cortex,
as an adaptive response to cortical injury and to provide toler-
ance to subsequent ischemic episodes.260,261 nNOS increases
during CSD,260 and the genes upregulated in this neuropro-
tective response are iNOS and HIF-1a.262 is is an example
of an immune memory process, as reviewed by Szentivanyi
et al,263 and may be a similar mechanism to that involved in
peripheral nerve injury and varicosity formation. Reversible
varicosity formation has also been noted for a number of con-
ditions, such as ischemia264,265 and toxic assault,266–268 depend-
ing on the severity and/or duration of the stimulus.
Preconditioning of neurons can also involve the forma-
tion of small protective varicosities. Subjecting cell cultures of
rat neurons to ischemic preconditioning269 resulted in the for-
mation of small varicosities in dendrites via a PSD-95 pathway
(Fig. 2A). ese were also reversible within four hours and
may have had a role in neuroprotection against NMDA
receptor-mediated toxicity. e use of black widow spider
venom to speed recovery from botulism neurotoxin resulted
in rapid varicosity formation (Fig. 2B) that (under sublethal
conditions) were reversible within 48hours.270
In a strikingly similar process to endogenously induced
varicosities, PBM has also been shown to cause MT disruption
and varicosity formation in the cytoskeleton of neurons.19,22 4
is has been demonstrated in cultured rat and murine DRG
neurons for a number of wavelengths, including 650 (Chow,
unpublished), 808,19 830,224 and 1064 nm (Chan, unpub-
lished). is MT disruption leads to a pain blockade eect.
Immunohistochemistry of DRG neuronal cultures shows the
interruption of cytoskeletal integrity within 5–10 minutes
following 30 or 60 seconds of laser irradiation. is eect
can be seen with confocal microscopy as the formation of
varicosities along the axon (Fig. 3A and B) and disruption
of fast axonal ow (Fig. 3E). Specically, b-tubulin from
the MTs accumulates in the varicosities as do mitochondria,
Figure 2. Formation of preconditioning neuroprotective varicosities: (A) immunouorescent images of neuronal cultures, showing control (a) and the
formation of varicosities (b) following ischemic preconditioning using nonharmful ox ygen and glucose deprivation for 30 minutes;269 (B) confocal laser
microsc opy images of stem cell-derived neurons stained with c alcein green, showing the formation of varicosities (arrows) within 22 minutes of the
application of black widow venom still apparent after 24 hours, but reducing after 48 hours. 270
Liebert et al
10 JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
Figure 3. C onfocal laser microscopy of axonal varicosities (arrows) produced by LLLT in cultured rat DRG neurons at wavelengths of 1064 nm (A) (Chan,
unpublished) and 830 nm (BF);19 (B) varicosit y formation after 120 seconds of LLLT; (C) control; (D) reversal of varicosities 24 hours af ter irradiation;
(E) magnied image of an axon showing a single varicosity formed after 30-second irradiation with mitochondria stained red; (F) control.
from which ATP is rapidly depleted. Importantly, this
disruption is temporary and reversible, with the axon return-
ing to its previous state within 24 hours (Fig. 3C). Other
eects of LLLT on unmyelinated nerve bers include the
fragmentation of the neurite in the growth cone,224 a decrease
in the number of neurolaments, and increases in the number
of M Ts. 271
Interestingly, MT disassembly is also evident in cells,
including neurons and lymphocytes, as a response to local7 7,7 9
and general272 anesthetics. is is characterized by the
Neuroprotective effects against POCD by photobiomodulation
11JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
formation of varicosities in axons, in response to local anes-
thetics79 (Fig. 4A and B) and cell shape changes in macro-
phages273 and the formation of blebs in 3T3 cells (Fig. 4C).77
ere is a question as to the primary target of LLLT
in neurons which will cause the cytoskeletal disruption and
varicosity formation. Several of the proteins involved in the
dynamic instability of MTs (including PrPC and PSD-95)
have the capability to undergo conformational change, which
could lead to MT instability. PBM could induce such a
structural change by direct absorption of the light energy by
the proteins or by the redox-sensing proteins responding to
reactive oxygen species (ROS), such as nitric oxide. A poten-
tial mechanism for neural protection could also be postulated
based on TRESK ion channels. e volume increase following
cytoskeleton modulation and varicosity formation caused by
LLLT will result in neural membrane stretch. Membrane ten-
sion is known to reversibly increase TRESK K+ currents in
the DRG.2 74 is has a dampening eect on excessive neu-
ron activation following injury and inammation by reducing
neural excitability.275 e inammatory response is reduced by
the downre gulation of the calc ium-activated ce ll stress cascade ,
including the unfolded protein response. is would have the
eect of producing a preconditioning eect to a llow the neuron
a more ecient response due to immune memory.262 TRESK
is phosphorylated by MT anity-regulating kinase276 and
also responsible for the phosphorylation of tau.277 In addition,
TRESK has a physical link with tubulin and possibly MTs,
at least in vitro.12 is suggests a (hypothetical) scaold of
TRESK/PrPC/MT, which could react to photons (PBM)
either directly or via another mechanism to facilitate MT
disassembly and varicosity formation.
A number of chemicals are known to destabilize MT
in a similar manner to PBM. Drugs such as colchicine and
nocodazole bind to tubulins and, therefore, prevent assembly
into MTs. Taxol and other taxane drugs bind to and stabi-
lize MTs preventing depolymerization, while demecolcine
depolymerizes MTs.278,279 As previously noted, anesthetics
are also known to interact with the cytoskeleton76–78 and
Figure 4. Varicosities and MT changes due to anesthetics: (A) light photomicrographs of the effect of 2 × 10 –3 M procaine on varicosity formation in
cultured neurites from time zero to (a) two hours (b), three hours (c), and four hours (d);79 (B) scanning electron micrograph of swellings (S) in the neurite
in response to 1 × 10-3 M procaine;79 (C) electron micrograph showing the formation of blebs on 3T3 cell sur face, due to the disruption of membrane-
associated MT and microlaments after treatment with 0.6 mM tetrac aine.77
Liebert et al
12 JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
can bind to tubulin and cause MT disassembly.80 Halo-
thane interferes with MT reassembly in peripheral nerves
in animal models,280 and chronic exposure can cause
behavioral impairment and neuronal damage including
reduced dendritic branching.281 Propofol causes reversible
retraction of neurites in cultured rat neurones, mediated by
GABAAR. Isourane can aect MT and neuronal laments
in astrocytes.64 e anesthetic sevourane has been shown
to produce transient hyperphosphorylation of tau in mice on
a single application, while repeated anesthetic led to a per-
sistent tau hyperphosphorylation and a signicant memory
impairment (POCD).84 e anesthetic propofol was also
shown to induce tau hyperphosphorylation in a mouse hip-
pocampus model of AD.86
Although small, reversible varicosities are seen as a
response to stress and are neuroprotective, continuation of the
assault or continued dysregulation of cytoskeleton assembly/
disassembly results in destructive cytoskeleton breakdown.
Axonal trauma can trigger major MT breakage, inhibiting
cargo transport to a greater extent than can be accommodated
by normal catastrophe and rescue.282 Damage by trauma may
not be readily repaired by the normal endogenous mechanisms,
leading to a more long-term impact on neuron function and
possibly damaged MTs, further accelerating the problem.65
is is exemplied by traumatic peripheral axonal injury
(dynamic stretch injury)246 that results in axonal swellings
(Fig. 5A). ese axonal swellings are also seen in head injury
trauma (Fig. 5B).246 In addition to the pathological conditions
in the peripheral axon, the same physiological mechanism can
occur in the axonal synapse and hippocampus, which involves
synaptic plasticity and long-term potentiation in memories
and learning, both linked with PSD-95.107,28 3
Chung et al284 demonstrated pathological varicosities in
sympathetic chronic pain when somatosensory nerves com-
municate with sympathetic nerves in the DRG (Fig. 5D).
Focal swellings or spheroids are also evident in ischemia,285
epilepsy,286 and brain tumor.287 Varicosities (also called
focal swellings, beading, or spheroids) are hallmarks and
often early indicators of neurodegenerative diseases,288 such
as AD182,285, 289–291 (Fig. 5F), PD292,293 (Fig. 5C), prion
disease,294 multiple sclerosis,295 Wallerian degeneration,296
rett syndrome,297 and children exposed to high levels of air
pollution, who show signs of early AD.231 Overexpression of
PrPC, which imitates prion disease,2 39 results in small con-
torted stumpy neurites with obvious swellings (Fig. 5E).
In summary, PBM may work well in a number of com-
plimentary ways to promote neuroprotection. PBM produces
cytoskeleton modulation and neuroprotective varicosities that
inhibit or reduce cargo transport and fast axonal ow, in the
same way as has been demonstrated for pain blockade.19,182
ese varicosities mimic endogenous varicosities, and thus
PBM may stimulate the body’s own neuroprotective mecha-
nism. Small reversible varicosities have been previously sug-
gested as a neuroprotective mechanism in animal models14, 255
and have been invoked as part of neuroprotection against
ischemia.269 is PBM stimulation may operate via photon
activation of redox signaling (mitochondrial or NADPH
at the cell membrane) or via direct protein conformational
changes (possibly in TRPV1)18 and cell signaling to the cyto-
skeleton via a (hypothetical) TRESK-PrPC-tau-tubulin scaf-
fold and would include the molecules PSD-95, cypin, and
MAPK (also known to be modulated by PBM)212,298 and
the transient phosphorylation of tau.14 is immune mem-
ory eect262 could protect neurons against anesthetic attack
on the cytoskeleton. PBM also has the eect of modulating
the inammatory response, by the regulation of the expres-
sion of iNOS196,199 and HIF-1a,204 the downregulation of the
inammatory cytokines IL-6, IL-1b, and TNF-a,208 and the
upregulation of growth factor IGF-1,201 all suspected to be
involved in POCD. PBM also modulates the cellular redox
balance by decreasing oxidative stress and increasing levels of
antioxidants,203,211 as well as the upregulation of mitochon-
drial function, biomarkers of which were found to be impor-
tant in POCD.111
Conclusion
Despite early equivocal studies, POCD is recognized as a sig-
nicant problem in the modern health-care system, aecting
elderly patients undergoing anesthetics and surgery. Although
most POCD appears to be reversible within weeks or months,
it nonetheless has an eect on the quality of life of patients
and an impact on health-care resources. ere is also a possi-
bility of long-term eects of POCD, including AD, in certain
patients. e impact of POCD will increase into the future
as medical and surgical procedures continue to improve and
surgery becomes lengthier and more common. With an aging
population, the patients most vulnerable to POCD are also
the group with the greatest increase in surgical procedures.
e cause of POCD appears multifactorial but may
involve similar mechanisms to AD, with which it shares some
characteristics and common molecular markers. Anesthetic
use and neuroinammation are implicated, with many mark-
ers for neuroinammation apparent in animal and clinical
studies.
MTs, and the cytoskeleton generally, have a role in
signal transduction, both as an initiator and a conduit. e
dynamic stability of MTs, together with their function in
directing neurite growth and in cellular signaling, gives the
cytoskeleton a role in the stability of the neuron and they
therefore have an allosteric role more generally in the nervous
system. is would include reaction to the stimuli of injury
and inammation, including anaesthesia and surgery, which
is in addition to any direct eect that anesthetics have on the
cytoskeleton of neurons. Assembly and disassembly of the
cytoskeleton is central to neuroplasticity and involves molecu-
lar switching. Disassembly and subsequent reassembly of MT
is responsible for the neuroprotective eect in hibernation,
in the CSD-associated migraine with aura, in the cortical
Neuroprotective effects against POCD by photobiomodulation
13JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
Figure 5. Pathological varicosities: (A) immunouorescent images of axonal swellings produced during dynamic stretch injury of cultured neurons,
stained for tubulin (a), tau (b), amyloid precursor protein (c), and neurolament (d);246 (B) immunohistochemical stain against amyloid precursor protein,
showing axonal varicosities in the corpus callosum of traumatic brain injur y cases, caused by motor vehicle collision (a, e, f ), falls (b, c), and blunt
force trauma (d);246 (C) confocal laser microscopy images of putamen tissue from Parkinson’s disease cases, showing varicosities, stained for tyrosine
hydroxylase (TH), a-synuclein (s-129), with a merged image;292 (D) electron micrograph of TH immune reactivity showing an axonal (synaptic) varicosity in
rat DRG as a result of sensor y and sympathetic interactions;28 4 (E) immunostained image of varicosity formation in a neuronal cell culture after exposure
to prion protein peptide 106–126, showing varic osities (arrows 1–5);239 (F) immunohistochemical stains showing varicosities and spheroids in a mouse
model of Alzheimer’s disease, stained for neurolament (a, b, c) and the spinal cord of an early onset Alzheimer’s disease c ase, stained for amyloid
precursor protein (d).289
Liebert et al
14 JOURNAL OF EXPERIMENTAL NEUROSCIENCE 2016:10
adaptive response to injury, and in neuroprotection against
toxic assault, such as NMDA and possibly anesthetics. Given
the role of MT in such neurodegenerative diseases as AD, PD,
and tauopathies, it is not unreasonable to suggest that similar
mechanisms could be important in POCD.
Since there is no available treatment for POCD, pre-
conditioning and neuroprotection would appear to be
the optimum intervention for its prevention. Although
neuroprotective drugs and cytokine antagonists have shown
some success in animal models, it is suggested that PBM
would be a viable option in preconditioning against POCD.
PBM has been shown to directly aect MT and to cause
small, reversible varicosities that aect cellular signaling,
fast axonal transport, and pain blockade. is could occur
via photoreceptors at the membrane such as opsins (neu-
ropsin), NADPH, or TRPV1, which could in turn interact
with tau and the MTs via ROS or via signal transduction
involving PrPC and/or PSD-95. e varicosities produced
by PBM mimic the endogenously produced varicosities that
are known to be neuroprotective against the large, destruc-
tive varicosities, swelling, and greater damage to the neuron.
us, PBM-generated varicosities act to precondition neurons
against damage in an analogous mechanism to the varicosities
produced during ischemic preconditioning. PBM is known
as a preconditioning treatment in other diseases and condi-
tions, such as macular degeneration, cardiovascular disease,
and muscle performance. Taken together with the success of
PBM in the prevention and treatment of animal models of
neurodegenerative disease, it is proposed that the use of PBM
preoperatively would have a preconditioning role for the pre-
vention of POCD in patients undergoing surgery, especially
in elderly, vulnerable patients.
Since POCD is not responsive to treatment, there is a
need to identify patients at risk of POCD, including iden-
tifying MCI and serum markers of POCD risk. is would
enable patients who would benet from PBM precondition-
ing to be identied, especially those elderly patients with
patterns of vulnerability to POCD, AD, and other forms of
dementia. is would, however, not preclude the more wide-
spread use of PBM on elderly surgical patients. PBM has
the benet of no identied harmful eects within the cor-
rect dose parameters and following contraindication recom-
mendations. Elderly surgical patients who would most benet
from PBM preconditioning could include patients with con-
ditions known or suspected to be related to POCD or AD
(including preexisting cognitive decline, MCI, type I and
type II diabetes, alcohol abuse, hypertension, and atheroscle-
rosis); patients with markers and potential markers of AD and
POCD (including b-amyloid, ApoE4, Ab42/tau ratio, CRP,
SELP, C3F, iNOS, cytochrome P450, aspartic acid, and
melatonin); patients with melanocortin signaling variations
(such as redheaded women); patients with photophobia, CSD
migraine with aura, and cluster headaches; and other patients
with TRESK polymorphisms.
Author Contributions
Wrote the rst draft of the manuscript: ADL. Contributed
to the writing of the manuscript: ADL, RC, BTB, and EV.
Agreed with the manuscript results and conclusions: ADL,
RC, BTB, and EV. Jointly developed the structure and argu-
ments for the paper: ADL and BTB. Made critical revisions
and approved the nal version: ADL, RC, BTB, and EV. All
the authors reviewed and approved the nal manuscript.
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Supplementary resources

  • ... One of the primary targets of PBM photons is believed to be the cytochrome C oxidase of the mitochondria, with the action of PBM being to increase ATP production and reactive oxygen species, which act on secondary signalling molecules to affect downstream pathways [14,15]. In addition, it has been shown that PBM affects non-mitochondrial receptors, such as ion channels and NADP oxidase in cell membranes, as well as having a direct influence on the cellular cytoskeleton (reviewed by [16]). ...
    ... The delay in response to PBM (14 days) suggests the latter, given that rapid bacteria growth would be expected to produce a faster response. The increased effect of infrared compared to red light might be due to increased penetration or to different cellular targets of the different wavelengths [16]. At the power density used to treat the mice, it is unlikely that there is any significant heating effect [30,31]. ...
    ... Light has a modulating effect on all types of organisms from bacteria to humans. In humans, this can be seen as increased depression in winter (seasonal affective disorder-SAD), in neonate jaundice, in the healing of wounds, in the increase in cardiac events after clock changes for daylight saving, in the latitude and month of conception for multiple sclerosis risk, and in the progression of Alzheimer's disease in nursing homes with and without natural light [16]. Light can be in the form of naturally occurring light or therapeutic applications such as bright light therapy for SAD, blue light for bilirubin, UVB for multiple sclerosis therapy, and PBMt (laser and LED). ...
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    Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.
  • ... PBM, delivered as low-level laser, has been shown to have a dramatic effect on the cytoskeleton structure of nerve cells, with the rapid formation of transient varicosities, and consequent nerve blockade for pain relief. [45][46][47][48][49] PBM also affects the cytoskeleton of other cells besides neurons, such as epithelial cells, 50 keratinocytes, 51 and fibroblasts, 52 and has been shown to have effects on protein conformation, including calcium ion channels. [53][54][55] PBM also has an effect on brain oscillation patterns, with changes to alpha, beta, gamma, delta, and theta waves in both mice 56 and humans 57 (El Khoury, et al., unpublished observations) and effects on the default mode network. ...
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    Objective: The objective of this review is to consider the dual effects of microbiome and photobiomodulation (PBM) on human health and to suggest a relationship between these two as a novel mechanism. Background: PBM describes the use of low levels of visible or near-infrared (NIR) light to heal and stimulate tissue, and to relieve pain and inflammation. In recent years, PBM has been applied to the head as an investigative approach to treat diverse brain diseases such as stroke, traumatic brain injury (TBI), Alzheimer's and Parkinson's diseases, and psychiatric disorders. Also, in recent years, increasing attention has been paid to the total microbial population that colonizes the human body, chiefly in the gut and the mouth, called the microbiome. It is known that the composition and health of the gut microbiome affects many diseases related to metabolism, obesity, cardiovascular disorders, autoimmunity, and even brain disorders. Materials and methods: A literature search was conducted for published reports on the effect of light on the microbiome. Results: Recent work by our research group has demonstrated that PBM (red and NIR light) delivered to the abdomen in mice, can alter the gut microbiome in a potentially beneficial way. This has also now been demonstrated in human subjects. Conclusions: In consideration of the known effects of PBM on metabolomics, and the now demonstrated effects of PBM on the microbiome, as well as other effects of light on the microbiome, including modulating circadian rhythms, the present perspective introduces a new term "photobiomics" and looks forward to the application of PBM to influence the microbiome in humans. Some mechanisms by which this phenomenon might occur are considered.
  • ... This technique has been gaining increasing popularity due to its wide range of beneficial results. Not only does it impart therapeutic benefits from wound healing 1 and pain relief 2 , PBM can also be used for retinoprotection 3 , neuroprotection 4 , synaptogensis 5 , and cognitive enhancement 6 . PBM uses red or near infrared (NIR) light in the 600-900 nm range at low levels of irradiance to cause photochemical changes within cells. ...
  • ... Effective anaesthetic methods should be selected to reduce the negative impacts such as POCD brought by the surgery. 7,8 Spinal anaesthesia refers to the injection of local anaesthetics into the subarachnoid or epidural space of the spinal canal to block the corresponding spinal nerve roots and produce anaesthetic effects in the dominating area. 9,10 At present, spinal anaesthesia is an anaesthetic method commonly used in scheduled orthopaedic surgery. ...
    Article
    Objective: To investigate the impacts of general and spinal anesthesia on short-term cognitive function and mental status in elderly patients undergoing orthopaedic surgery. Study design: An experimental study. Place and duration of study: Department of Anesthetics, the Central People's Hospital of Tengzhou City, Shandong Province, China, from December 2016 to December 2017. Methodology: A total of 80 elderly patients undergoing orthopaedic surgery were selected and randomly divided into the observation group and the control group, 40 cases in each group. The observation group underwent spinal anesthesia, and the control group underwent general anaesthesia. Eye opening time, language presentation time etc.in the two groups were compared. Results: The eye opening time and language presentation time in observation group were all lower than those in control group (both p<0.001). At 1, 3 and 6 hours after surgery, the mini-mental state examination (MMSE) scores and the amplitudes of the P300 wave of observation group were all higher than those of the control group (all p<0.001), the latencies of the P300 wave in observation group were all lower than control group (all p<0.001). At 24h after surgery, the number of cases suffering postoperative cognitive dysfunction (POCD) in the observation group was lower than that of the control group (p=0.039). Conclusion: Compared with general anaesthesia, spinal anesthesia can effectively shorten the eye opening time and language presentation time in elderly patients undergoing orthopaedic surgery. It also has few impacts on the short-term cognitive function and mental status of such patients, with lower incidence of POCD.
  • ... . From the literature, formation of axonal varicosities occurs as a response to multiple stimuli and stressors, including mechanical stress, axonal damage, heat and cold, toxins, and anesthetics(47)(48)(49)(50) as well as in neurodegenerative diseases(51,52). Human MNs derived from ALS patient iPSCs revealed neurofilament aggregation as an early ALS pathological event which underlies MN pathology(53). ...
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    There has been a tremendous amount of research into the causes of Amyotrophic Lateral Sclerosis (ALS), but yet very few treatment options beyond amelioration of symptoms. A holistic approach has shown anecdotal evidence of slowing disease progression and this treatment, known as the Deanna Protocol (DP), postulates that ALS is a metabolic disease caused by glutamate that induces toxicity. In this study, glutamate exposure to human motoneurons was investigated and found not to significantly affect cell viability or electrophysiological properties. However, varicosities were observed in axons suggestive of transport impairment that was dose dependent for glutamate exposure. Surprisingly, a subset of the components of the DP eliminated these varicosities. To verify this finding a human SOD1 patient-derived iPSC line was examined and significant numbers of varicosities were present without glutamate treatment, compared to the iPSC control, indicating the possibility of a common mechanism despite different origins for the varicosities. Importantly, the DP ameliorated these varicosities by over 70% in the patient derived cells as well. These results are consistent with much of the literature on ALS and give hope for treatment not only for arresting disease progression using compounds considered safe but also the potential for restoration of function.
  • ... Moreover, there are various risk factors for POCD, including age, cognitive function before surgery, duration of the surgery, and respiratory complications and infection after surgery (4). Recently, POCD has been considered a serious problem affecting people's health and has an influence on both the outcome and elevated costs of patients, but until now, only a few useful treatments have been discovered (5). POCD can last for several days or even several years; consequently, the quality of life of the patients is extremely disrupted, there is an increase in hospitalization and in extra hospital nursing expenses, and POCD is also blamed for increasing morbidity and mortality during surgery (2). ...
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    Postoperative cognitive dysfunction (POCD) is a severe complication characterized by cognitive dysfunction following anesthesia and surgery. The aim of the present study was to investigate the effects of β‑site amyloid precursor protein cleavage enzyme 1 (BACE1) gene silencing on isoflurane anesthesia‑induced POCD in immature rats via the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway. Rat models were established and then transfected with BACE1 small interfering RNA and wortmannin (an inhibitor of PI3K). Blood gas analysis was performed, and a series of behavioral experiments were conducted to evaluate the cognitive function, learning ability and locomotor activity of rats. Reverse transcription quantitative polymerase chain reaction and western blot analysis were employed to determine the mRNA and protein expression of the associated genes. An ELISA was used to detect the inflammatory indicators and the content of amyloid precursor protein (APP) and amyloid‑β (Aβ). Apoptosis of the hippocampal CA1 region was observed by terminal deoxynucleotidyl transferase dUTP nick‑end labeling staining. Initially, it was revealed that the percentage of stagnation time in rats was increased by BACE1 gene silencing; the escape latency and swimming distance were markedly reduced from the 4th to the 6th day, the time the rats spent in first passing the target area was shortened, and the times of passing the target area were increased by BACE1 gene silencing, demonstrating that BACE1 gene silencing enhanced the spatial memory ability of rats. Additionally, it was determined that silencing BACE1 improved the pathological state induced by isoflurane anesthesia in immature rats, and attenuated the inflammatory response and the levels of APP and Aβ in hippocampal tissues. Furthermore, it was suggested that silencing BACE1 may have promoted the activation of the PI3K/Akt signaling pathway, thereby inhibiting the apoptosis of the hippocampal CA1 region. Taken together, these results indicated that BACE1 gene silencing may improve isoflurane anesthesia‑induced POCD in immature rats by activating the PI3K/Akt signaling pathway and inhibiting the Aβ generated by APP.
  • ... These sequences of events are often a prelude for the morphological changes in ASCs responsible for neuronal differentiation and impulse transmission. 79 However, it was unsuccessful in differentiating ASCs to smooth muscle cells at a fluence and wavelength of 5 J/cm 2 and 636 nm, even in the presence of retinoic acid. 80 Perhaps, these conflicting data motivate us in testing a wide range of laser parameters on ASCs for differentiation to body cell types in vitro. ...
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    Background: Neurological diseases and disorders pose a challenge for treatment and rehabilitation due to the limited capacity of the nervous system to repair itself. Adipose stem cells (ASCs) are more pliable than any adult stem cells and are capable of differentiating into non-mesodermal tissues, including neurons. Transdifferentiating ASCs to specific neuronal lineage cells enables us to deliver the right type of cells required for a replacement therapy into the nervous system. Methods: Several methodologies are being explored and tested to differentiate ASCs to functional neurons and glia with cellular factors and chemical compounds. However, none of these processes and prototypes has been wholly successful in changing the cellular structure and functional status of ASCs to become identical to neuroglial cells. In addition, successful integration and functional competence of these cells for use in clinical applications remain problematic. Photobiomodulation or low-level laser irradiation has been successfully applied to not only improve ASC viability and proliferation but has also shown promise as a possible enhancer of ASC differentiation. Conclusions: Studies have shown that photobiomodulation improves the use of stem cell transplantation for neurological applications. This review investigates current neuro-differentiation inducers and suitable methodologies, including photobiomodulation, utilizing ASCs for induction of differentiation into neuronal lineages.
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    Background: There is a wide range of animal models available today for studying chronic pain associated with a variety of etiologies and an extensive list of clinical manifestations of peripheral neuropathies. Photobiomodulation is a new tool for the treatment of pain in a convenient, noninvasive way. Objective: The aim of this work is to elucidate the effects of infrared light-emitting diodes (LEDs) on behavioral responses to nociceptive stimuli in chronic pain models. Methods: Forty-eight Swiss male mice weighing 25 to 35 g were used. Two chronic pain models, ischemia-reperfusion (IR) and spared spinal nerve injury, were performed and then treated with infrared LED irradiation (390 mW, 890 nm, 17.3 mW/cm2 , 20.8 J/cm2 , for 20 minutes). The behavioral tests used were a mechanical hypersensitivity test von Frey test) and a cold allodynia test (acetone test). Results: The results showed that, in the IR model, the infrared LED had a significant effect on mechanical stimulation and cold allodynia on every day of treatment. In the spared nerve injury model, an analgesic effect was observed on every treatment day (when started on the 3rd and 7th days after the surgery). In both models, the effect was abolished when the treatment was interrupted. Conclusions: These findings suggest that photobiomodulation therapy may be a useful adjunct treatment for chronic pain.
Literature Review